Preclinical and clinical studies suggest that antidepressants with a combined mechanism of action (e.g., combination of a selective serotonin-reuptake inhibitor (SSRI) and a norepinephrine reuptake inhibitor) may be more effective than either agent alone in achieving remission (Nelson et al 2004). Thus, it stands to reason that other combinations of antidepressants with other mechanisms of action when combined may have a synergistic effect that is superior to an antidepressant with a single mechanism of action. Preclinical and clinical studies suggest that the dopaminergic system may play a major role in the pathophysiology of depression. Preclinical studies suggest synergistic antidepressant effects with the combination of a SSRI and a selective D3 receptor agonist in animal models of depression. Similarly, preliminary clinical studies suggest synergism with combination treatment that affects the serotonin and dopamine systems. Together, these data suggest that treatments which affect the serotonin and dopamine systems will be more effective than agents which use a single mechanism. We are currently comparing the combination of a selective dopaminergic agonist and a SSRI in patients with treatment-resistant major depression. This study is still ongoing and actively recruiting subjects. The study results are not yet available as the study has not been completed. To our knowledge, this is the only controlled double-blind study to date that is examining the efficacy of a serotonin and dopamine combination given from the start of treatment. Patients, ages 18 years or older, with a diagnosis of major depression are being randomized to the combination of a selective dopaminergic receptor agonist and a SSRI or either drug alone for a period of 6 weeks.